The metabotropic glutamate receptors (mGluRs) play critical roles in regulating transmission in the hippocampal formation and these actions are important for both acute regulation of hippocampal function and long-lasting forms of synaptic plasticity that may underlie hippocampal-dependent learning and memory. The mGluR5 subtype of mGluR regulates NMDA receptor currents and both long-term potentiation (LTP) and long- term depression (LTD) of transmission in hippocampal area CA1. We have shown that highly selective positive allosteric modulators (PAMs) of mGluR5 enhance both hippocampal LTP and LTD and maintain a strict dependence of both forms of hippocampal synaptic plasticity on specific patterns of activity of presynaptic afferents. This provides an excellent profile for potential cognition-enhancing agents. Exciting progress in developing systemically active mGluR5 PAMs that cross the blood brain barrier makes it possible to rigorously test the hypothesis that selective potentiation of mGluR5 signaling in vivo will enhance hippocampal-dependent forms of learning and memory. In addition to a role of mGluR5 in regulating hippocampal function, we have shown that another group of mGluRs, termed group II mGluRs (mGluR2 and mGluR3), participate in a novel form of glial-neuronal communication in the hippocampus in which activation of mGluRs on astrocytes leads to release of adenosine and reduction of glutamate release from neighboring glutamate synapses. We postulate that this astrocytic response is mediated by the mGluR3 subtype and that activation of mGluR3 could have effects on hippocampal synaptic plasticity that are opposite to those of mGluR5. If so, mGluR3 activation could impair hippocampal LTP and selective antagonists of mGluR3 could have cognition-enhancing effects. We will perform a series of studies to test the hypothesis that mGluR5 PAMs enhance hippocampal-dependent cognitive function and reverse learning deficits in genetically altered mice in which glutamatergic transmission is impaired by selective reductions in expression of the NMDA subtype of glutamate receptor. In addition, we will test the hypothesis that mGluR3 is responsible for this novel form of astrocytic-neuronal communication and that antagonists of mGluR3 can enhance synaptic transmission in the hippocampus and enhance hippocampal-dependent LTP. PUBLIC HEALTH RELEVANCE: A family of neurotransmitter receptors called metabotropic glutamate receptors (mGluRs) have emerged as exciting new drug targets for development of medicines for treatment of a variety of psychiatric and neurological disorders, including Alzheimer's disease, autistic disorders, and schizophrenia. We have discovered new drug like molecules that selectively interact with these receptors. Studies are proposed to determine the effects of these novel molecules in brain circuits that may be critically involved in treatment of these brain disorders.